Structural Determinants of Aldosterone Binding Selectivity in the Mineralocorticoid Receptor

Rogerson, Fraser M.; Dimopoulos, Nektaria; Sluka, Pavel; Chu, Simon; Curtis, Andrea J.; Fuller, Peter J.

doi:10.1074/jbc.274.51.36305

Cited by 64 publications

(45 citation statements)

References 33 publications

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“…Compared with the other receptors, the AR ligand-binding pocket seems to be shifted up toward helices 1 and 3, which contributes to selectivity of the AR for androgens. The relative position of the ligand-binding pocket provides a structural basis for the importance of residues outside of the pocket, which are critical for the integrity of the LBD (Rogerson et al, 1999 Rogerson and Fuller, 2003). A glutamine-rich region in the AR N terminus is necessary and sufficient for recruiting coactivators such as SRC-1 (Bevan et al, 1999).…”

Section: Structurementioning

confidence: 99%

International Union of Pharmacology. LXV. The Pharmacology and Classification of the Nuclear Receptor Superfamily: Glucocorticoid, Mineralocorticoid, Progesterone, and Androgen Receptors

Wardell

Burnstein

et al. 2006

Pharmacological Reviews

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254

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Section: Structurementioning

confidence: 99%

International Union of Pharmacology. LXV. The Pharmacology and Classification of the Nuclear Receptor Superfamily: Glucocorticoid, Mineralocorticoid, Progesterone, and Androgen Receptors

Wardell

Burnstein

et al. 2006

Pharmacological Reviews

Self Cite

359

254

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“…To examine ligand binding to the MR, we created a series of chimeras between the MR and GR LBDs (Rogerson et al 1999). The chimeras were designed by dividing the LBDs into four equivalent sections.…”

Section: Spironolactone Competition For [ 3 H]-dexamethasone Bindingmentioning

confidence: 99%

“…Apart from the steroid backbone, the two structures are quite dissimilar: the aldosterone molecule contains a hemiketal side-chain between C 11 and C 18 , whereas spironolactone contains a lactone ring at C 17 and a sulfhydryl ester side-chain at C 7 . In previous work we investigated structural determinants of aldosterone binding specificity using chimeras created between the LBDs of the MR and GR (Rogerson et al 1999). We identified a region in the MR LBD, between amino acids 804 and 874, that is critical for the specificity of aldosterone binding to the MR.…”

Section: Introductionmentioning

confidence: 99%

Determinants of spironolactone binding specificity in the mineralocorticoid receptor

Rogerson¹,

Yao²,

Smith³

et al. 2003

Journal of Molecular Endocrinology

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Spironolactone is a mineralocorticoid receptor (MR) antagonist in clinical use. The compound has a very low affinity for the glucocorticoid receptor (GR). Determinants of binding specificity of spironolactone to the MR were investigated using chimeras created between the ligand-binding domains (LBDs) of the MR and the GR. These chimeras had previously been used to investigate aldosterone binding specificity to the MR. Spironolactone was able to compete strongly for [3 H]-aldosterone and [ 3 H]-dexamethasone binding to a chimera containing amino acids 804-874 of the MR, and weakly for [ 3 H]-dexamethasone binding to a chimera containing amino acids 672-803 of the MR. Amino acids 804-874 were also critical for aldosterone binding specificity. Models of the MR LBD bound to aldosterone and spironolactone were created based on the crystal structure of the progesterone receptor LBD. The ligand-binding pocket of the MR LBD model consisted of 23 amino acids and was predominantly hydrophobic in nature. Analysis of this model in light of the experimental data suggested that spironolactone binding specificity is not governed by amino acids in the ligand-binding pocket.

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“…Sequence analysis reveals a strong homology between the hMR-and the human glucocorticoid receptor (hGR)-LBDs (56%). Recently, chimeras were made between hMR and hGR-LBD to characterize ligand-binding specificity (Rogerson et al, 1999). A region of the hMR-LBD that extends between amino acids 804 and 874 that is crucial for aldosterone binding specificity has been identified.…”

mentioning

confidence: 99%

A Single Amino Acid Mutation of Ala-773 in the Mineralocorticoid Receptor Confers Agonist Properties to 11β-Substituted Spirolactones

et al. 2000

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Sequence analysis revealed a strong homology between the ligand-binding domain (LBD) of the human mineralocorticoid receptor (hMR) and glucocorticoid receptor (hGR). Nevertheless, steroids with bulky C11-substituents bind to hGR, unlike hMR. In this report, a mutant hMR, in which the residue Ala-773 facing the C11 steroid position was replaced by a glycine (A773G), was assayed for its capacity to bind steroids, to interact with receptor coactivators, and to stimulate transcription. The capacity of A773G to bind aldosterone and C11-substituted spirolactones was the same as that of the wild-type receptor. The agonist properties of aldosterone, as well as the antagonist feature of compounds bearing a 11␤-allenyl group and a C17-ketone function, remain unchanged. In contrast, C11-substituted steroids with a 17␥-lactonic ring displayed antagonist properties with hMR and acted as potent agonists with A773G. An agonist-dependent hMR interaction with SRC-1 was observed for both the wild-type and the mutant receptors. The hMR activation process is discussed in the light of the hMR-LBD homology model based on the structural data of the human progesterone receptor LBD.The mineralocorticoid receptor (MR) belongs to a large family of ligand-activated transcription factors that includes the other steroid receptors as well as thyroid, retinoid, and vitamin D receptors and also orphan receptors whose ligands have not yet been identified. All the members of this large family are characterized by a conserved DNA binding domain and a C-terminal ligand-binding domain (LBD) essential for chaperone protein interaction, receptor dimerization, and hormone-dependent transactivation (Arriza et al., 1987;Evans, 1988). Recently, the crystal structure of ligand-free and liganded LBDs has been solved for several nuclear receptors (NRs) (Bourguet et al., 1995;Renaud et al., 1995;Wagner et al., 1995;Wurtz et al., 1996;Brozowski et al., 1997). These crystal structures reveal a triple-layered antiparallel ␣-helical sandwich fold surrounding the ligand-binding cavity. The major difference between the ligand-free and the agonist-bound LBD is the folding back of the helix H12 toward the LBD core, allowing the binding of transcriptional coactivators (Nichols et al., 1998). Moreover, the helix H12 was demonstrated to be differently positioned after antagonist binding, preventing the coactivator-receptor interaction (Nichols et al., 1998). A three-dimensional model of the human MR (hMR)-LBD, based on the human retinoic acid receptor (hRAR␥-LBD) crystal structure, has recently been proposed that allows the docking of various ligands within the ligand-binding cavity (Fagart et al., 1998). The identification of several amino acid residues involved in the interaction with agonists and antagonists has been made by mutagenesis. Gln-776 and Arg-817, two polar residues highly conserved within the steroid receptor family, anchor the C3-ketone function, common in mineralocorticoid agonist and antagonist ligands. At the opposite side of the ligand-bindin...

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Structural Determinants of Aldosterone Binding Selectivity in the Mineralocorticoid Receptor

Cited by 64 publications

References 33 publications

International Union of Pharmacology. LXV. The Pharmacology and Classification of the Nuclear Receptor Superfamily: Glucocorticoid, Mineralocorticoid, Progesterone, and Androgen Receptors

International Union of Pharmacology. LXV. The Pharmacology and Classification of the Nuclear Receptor Superfamily: Glucocorticoid, Mineralocorticoid, Progesterone, and Androgen Receptors

Determinants of spironolactone binding specificity in the mineralocorticoid receptor

A Single Amino Acid Mutation of Ala-773 in the Mineralocorticoid Receptor Confers Agonist Properties to 11β-Substituted Spirolactones

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